The purpose of this research is to characterize the autoregulatory mechanism of the hypothalamic oxytocin (OT) system on the systemic release of OT during reproductive states. OT is synthesized by magnocellular cells (MNCs) in the supraoptic (SON) and paraventricular nuclei. OT is released into the general circulation to induce uterine contraction during parturition and contraction of mammary glands during milk ejection. The release of OT is, therefore, essential for birth and normal growth of offspring. The systemic release of OT is largely regulated by the somato-dendritic release of OT that is elicited by physiological stimuli, such as parturition and suckling. The somato-dendritic release OT on OT MNCs is thought to be mediated by the OT receptor (OTR) on OT MNCs themselves via an autocrine-paracrine mechanism. Despite this commonly accepted notion, our preliminary study using OTR reporter mice found no OTR in OT MNCs in the SON; however, OTR was found in non-OT cells in the perinuclear zone (PNZ), the area immediately dorsal to the SON. Moreover, these OTR cells have processes projecting into the SON. Based upon reports in the literature and our preliminary results, we hypothesize that: 1) OTR cells in the PNZ are GABAergic interneurons for OT MNCs in the SON; and 2) GABA inputs from OTR cells become stimulatory due to increase in intracellular chloride concentration in OT MNCs in lactating females. We will use an integrative multidisciplinary approach that includes electrophysiology combined with chemogenetic manipulation of neural activity, neural tracing, immunocytochemistry on transgenic mouse models to explicitly test our hypotheses. The findings from these studies will provide new information concerning the regulation of OT release and the neural adaptations that are necessary for proper parturition and lactation.